EP2150253A2 - Verwendung von 4-cyclopropylmethoxy-n-(3,5-dichlor-1-oxidopyridin-4-yl)-5-(methoxy)-pyridin-2-carboxamid zur behandlung von rückenmarksverletzungen - Google Patents

Verwendung von 4-cyclopropylmethoxy-n-(3,5-dichlor-1-oxidopyridin-4-yl)-5-(methoxy)-pyridin-2-carboxamid zur behandlung von rückenmarksverletzungen

Info

Publication number: EP2150253A2
Authority: EP; European Patent Office
Prior art keywords: carboxamide; dichloro; cyclopropylmethoxy; methoxy; pyridine
Prior art date: 2007-04-19
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Granted

Application number

EP08787962A

Other languages

English (en)

French (fr)

Other versions

EP2150253B1 (de

Inventor

Philippe Delay-Goyet

Badia Ferzaz

Jocelyne Lolivier

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Sanofi SA

Original Assignee

Sanofi Aventis France

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2007-04-19

Filing date

2008-04-16

Publication date

2010-02-10

2008-04-16 Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France

2008-04-16 Priority to PL08787962T priority Critical patent/PL2150253T3/pl

2008-04-16 Priority to SI200830270T priority patent/SI2150253T1/sl

2010-02-10 Publication of EP2150253A2 publication Critical patent/EP2150253A2/de

2011-03-30 Application granted granted Critical

2011-03-30 Publication of EP2150253B1 publication Critical patent/EP2150253B1/de

2011-06-28 Priority to CY20111100611T priority patent/CY1111779T1/el

Status Active legal-status Critical Current

2028-04-16 Anticipated expiration legal-status Critical

Links

Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system

Definitions

the present invention relates to the use of 4-cyclopropylmethoxy- / N- (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide in hydrate form. solvate, base or acid addition salt for the preparation of a medicament for the treatment of traumatic spinal cord injury.
4-cyclopropylmethoxy- ⁇ - (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide or also called ⁇ / - (3,5-dichloro-1 -oxydo-4-pyridinio) ⁇ 4-cyclopropylmethoxy-5-methoxypyridine-2-carboxamide, is known to enter the composition of drugs for the treatment of various pathologies, including joint inflammation, arthritis, rheumatoid arthritis. This compound, in hemihydrate form, is described for example in WO95 / 04045 (compound referenced FR).
PDE 4 phosphodiesterases 4
a first object of the invention therefore relates to the use of 4-cyclopropylmethoxy- ⁇ - (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide for the preparation of a medicament for the treatment of traumatic spinal cord injury.
the use of 4-cyclopropylmethoxy- / N- (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide can be in the form of a base or an acid addition salt.
the salts that can be used in the context of the invention can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of 4-cyclopropylmethoxy- ⁇ / - (3,5 dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide are also part of the invention.
(methoxy) pyridine-2-carboxamide according to the invention can also be in the form of hydrate or solvate.
hydrate or solvate is meant the combination or combination of one or more molecules of 4-cyclopropylmethoxy- ⁇ - (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine -2-carboxamide with one or more molecules of water or solvent.
spinal cord trauma means acute or chronic pathologies which have an external origin and which destroy the spinal cord and / or the spinal neurons, and which occur for example during a fall or a shock. , a crash or a traffic accident.
a second subject of the invention relates to a pharmaceutical composition
a pharmaceutical composition comprising, as active principle, 4-cyclopropylmethoxy- ⁇ - (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide, and one or more pharmaceutically acceptable excipients.
composition used according to the invention comprises an effective dose of the active ingredient.
the daily doses of active ingredient that can be used according to the invention are from 0.001 to 10 mg / day.
the dosage appropriate to each patient is determined by the physician according to the mode of administration, the age, the weight and the response of said patient.
the doses depend on the desired effect, the duration of treatment and the route of administration used.
excipients are selected according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
composition can be administered orally, parenterally (including intrathecally), or rectally.
Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. , by inhalation, topical, transdermal, subcutaneous, intramuscular, intravenous or intrathecal administration forms, rectal administration forms and implants.
the active ingredients according to the invention can be used in creams, gels, ointments or lotions.
the active ingredient is mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.
pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.
the tablets can be coated with sucrose, a cellulose derivative or other materials suitable for coating.
the tablets can be made by various techniques, such as direct compression, dry or wet granulation or hot melt.
aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible agents, for example propylene glycol or butylene glycol, are used.
a unit form of administration of 4-cyclopropylmethoxy- ⁇ - (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide in the form of tablet includes the following ingredients: 4-cyclopropylmethoxy- / N- (3,5-dichloro-1-oxido-pyridin-4-yl)
the Beam Balance test consists of placing the mouse at the end of a horizontal bar 30 cm long and 1.5 cm wide, raised 20 cm from the ground. The time required for the mouse to reach the opposite end of the beam is measured. The test is stopped after 12 seconds. If the animal falls or does not complete the test, the maximum time is recorded.
mice Female OF1 mice (Iffa Credo Lyon, France) of 12 to 14 g and aged 34 weeks are placed in experimental cages (32 X 21 X 14 cm) provided with food and water at will, at controlled temperature. 22 ⁇ 1 ° C.
mice are pre-apprenticed to familiarize themselves with the assessment test and enable them to achieve an optimal and identical level of performance.
This trauma consists of a lesion of the spinal cord located at the thoracic vertebra Th8.
the lesion is generated by 3 successive freeze-thaw cycles by applying liquid nitrogen.
Group 1 (without trauma) consists of control animals that are not subject to any trauma.
- Group 2 (trauma only) consists of traumatized animals given a daily dose of vehicle (methylcellulose (MC) (0.6%) + tween-80 (0.5%) in water).
vehicle methylcellulose (MC) (0.6%) + tween-80 (0.5%) in water).
Table 1 shows that traumatized animals curatively administered 4-cyclopropylmethoxy- ⁇ - (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide (group 3) reach the end of the bar more quickly than the traumatized animals to which this compound was not administered (group 2).
Example 2 An experiment similar to that of Example 1 was carried out by administering to O. mice (Charles River, France) of 12 to 14 g and 34 weeks old of ((4R) -4- [3- (Cyclopentyloxy) - 4-methoxyphenyl] pyrrolidin-2-one), in the treatment of traumatic spinal cord injury.
mice were tested in the Beam Balance test, according to operating conditions identical to those described previously.
Group A (without trauma) consists of control animals that are not subject to any trauma.
Group B (trauma alone) consists of traumatized animals to which one dose per vehicle day (PEG200 2%) is administered.
group deficit% (C) [(average group C travel time) - (average group A travel time)] / [(average group B travel time) -
Group A non-traumatized animals
Group B traumatized animals treated with the vehicle
Group C traumatized animals treated with (R> (-) - Rolipram
a value greater than 100% indicates that the group of evaluated mice performed, on average, the course in a time greater than that achieved, on average, by the group of traumatized mice treated with the vehicle.
Group C traumatized animals treated with (f? J - (-) - Rolipram.
Group 3 traumatized animals treated with 4-cyclopropylmethoxy- ⁇ - (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide.
the emetic power of 4-cyclopropylmethoxy- ⁇ - (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide was evaluated in ferrets. Two groups of ferrets were used, the first receiving vehicle (PEG200) and the second one 4-cyclopropylmethoxy- ⁇ / - (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide in vehicle solution (PEG 200), by oral gavage, at doses of 0.05 mg / kg and 0.1 mg / kg. The animals were observed continuously for 2 hours after administration and then once an hour until 6 hours after administration. Clinical signs (especially retching and vomiting) have been noted.
the emetic power of (f?) - (-) - rolipram has been evaluated in ferrets.
Two groups of ferrets were used, the first receiving vehicle (PEG200) and the second one 4-cyclopropylmethoxy- ⁇ / - (3,5-dichloro-1-oxido-pyridin-4-yl) -5- (methoxy) pyridine-2-carboxamide in vehicle solution (PEG 200), by oral gavage, at doses of 0.05 mg / kg and 0.1 mg / kg.
the animals were observed continuously for 2 hours after administration and then once an hour until 6 hours after administration. Clinical signs have been noted.
(methoxy) pyridine-2-carboxamide is useful in the preparation of a medicament for the treatment of nervous system trauma, such as trauma to the spinal cord, such as trauma during a fall, shock or accident. automobile or brain trauma, while avoiding possible emitting effects.
nervous system trauma such as trauma to the spinal cord, such as trauma during a fall, shock or accident. automobile or brain trauma, while avoiding possible emitting effects.

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Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
Epidemiology (AREA)
Neurosurgery (AREA)
Organic Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Neurology (AREA)
Biomedical Technology (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Pyridine Compounds (AREA)

EP08787962A 2007-04-19 2008-04-16 Verwendung von 4-cyclopropylmethoxy-n-(3,5-dichlor-1-oxidopyridin-4-yl)-5-(methoxy)-pyridin-2-carboxamid zur behandlung von rückenmarksverletzungen Active EP2150253B1 (de)

Priority Applications (3)

Application Number	Priority Date	Filing Date	Title
PL08787962T PL2150253T3 (pl)	2007-04-19	2008-04-16	Zastosowanie 4-cyklopropylometoksy-N-(3,5-dichloro-1-oksydo-pirydyn-4-ylo)-5-(metoksy)pirydyno-2-karboksamidu do leczenia urazów rdzenia kręgowego
SI200830270T SI2150253T1 (sl)	2007-04-19	2008-04-16	Uporaba 4-ciklopropilmetoksi-N-(3,5-dikloro-1-oksido-piridin-4-il)-5-(mekoksi) piridin-2-karboksamida za zdravljenje poškodb hrbtenjače
CY20111100611T CY1111779T1 (el)	2007-04-19	2011-06-28	Χρηση του 4-κυκλοπροπυλομεθοξυ-ν-(3,5-διχλωρο-1-οξειδο-πυριδιν-4-υλο)-5-(μεθοξυ)πυριδινο-2-καρβοξαμιδιου για τη θεραπευτικη αντιμετωπιση των τραυματισμων του νωτιαιου μυελου

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
FR0702851A FR2915098B1 (fr)	2007-04-19	2007-04-19	Utilisation du 4-cyclopropylmethoxy-n-(3,5-dichloro-1-oxydo- pyridin-4-yl)-5-(methoxy)pyridine-2-carboxamide pour le traitement des traumatismes de la moelle epiniere
PCT/FR2008/000533 WO2008145840A2 (fr)	2007-04-19	2008-04-16	Utilisation du 4-cyclopropylmethoxy-n-(3,5-dichloro-1 -oxydo- pyridin-4-yl)-5-(methoxy)pyridine-2-carboxamide pour le traitement des traumatismes de la moelle epiniere

Publications (2)

Publication Number	Publication Date
EP2150253A2 true EP2150253A2 (de)	2010-02-10
EP2150253B1 EP2150253B1 (de)	2011-03-30

Family

ID=38779706

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP08787962A Active EP2150253B1 (de)	2007-04-19	2008-04-16	Verwendung von 4-cyclopropylmethoxy-n-(3,5-dichlor-1-oxidopyridin-4-yl)-5-(methoxy)-pyridin-2-carboxamid zur behandlung von rückenmarksverletzungen

Country Status (33)

Country	Link
US (1)	US8592443B2 (de)
EP (1)	EP2150253B1 (de)
JP (1)	JP5386477B2 (de)
KR (1)	KR101470043B1 (de)
CN (1)	CN101674829B (de)
AR (1)	AR066106A1 (de)
AT (1)	ATE503481T1 (de)
AU (1)	AU2008257321B2 (de)
BR (1)	BRPI0810446A2 (de)
CA (1)	CA2684172C (de)
CL (1)	CL2008001134A1 (de)
CY (1)	CY1111779T1 (de)
DE (1)	DE602008005873D1 (de)
DK (1)	DK2150253T3 (de)
EA (1)	EA015355B1 (de)
ES (1)	ES2363056T3 (de)
FR (1)	FR2915098B1 (de)
HR (1)	HRP20110459T1 (de)
IL (1)	IL201451A (de)
JO (1)	JO2662B1 (de)
MA (1)	MA31369B1 (de)
ME (1)	ME00934B (de)
MX (1)	MX2009011285A (de)
MY (1)	MY146657A (de)
NZ (1)	NZ580483A (de)
PA (1)	PA8776601A1 (de)
PL (1)	PL2150253T3 (de)
PT (1)	PT2150253E (de)
PY (1)	PY08013253A (de)
SI (1)	SI2150253T1 (de)
TW (1)	TWI411435B (de)
UY (1)	UY31033A1 (de)
WO (1)	WO2008145840A2 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
FR2915099B1 (fr)	2007-04-19	2009-06-05	Sanofi Aventis Sa	Utilisation du 4-cyclopropylmethoxy-n-(3,5-dichloro-1-oxydo- pyridin-4-yl)-5-(methoxy)pyridine-2-carboxamide pour le traitement des traumatismes craniens
CN104955820A (zh) *	2012-11-28	2015-09-30	赛诺菲	4-(环丙基甲氧基)-n-(3,5-二氯-1-氧化-吡啶-4-基)-5-甲氧基吡啶-2-甲酰胺的制备方法
BR112015011849A2 (pt) *	2012-11-28	2017-07-11	Sanofi Sa	método de preparação de formas de cristal de 4 (ciclopropilmetoxi)-n-(3,5-dicloro-1-oxidopiridin-4-il)-5-metoxipiridina-2-carboxamida e formas de cristal da mesma
EP4281065A1 (de)	2021-01-20	2023-11-29	Alto Neuroscience, Inc.	Verbesserung der camp-signalisierung als kombinationsarzneimittelstrategie zur behandlung von depression und verwandten erkrankungen
WO2025079694A1 (ja) *	2023-10-12	2025-04-17	株式会社メドレックス	経皮吸収組成物

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2007
- 2007-04-19 FR FR0702851A patent/FR2915098B1/fr not_active Expired - Fee Related
2008
- 2008-04-15 PA PA20088776601A patent/PA8776601A1/es unknown
- 2008-04-16 AU AU2008257321A patent/AU2008257321B2/en not_active Ceased
- 2008-04-16 BR BRPI0810446-8A2A patent/BRPI0810446A2/pt not_active IP Right Cessation
- 2008-04-16 AT AT08787962T patent/ATE503481T1/de active
- 2008-04-16 DK DK08787962.3T patent/DK2150253T3/da active
- 2008-04-16 CA CA2684172A patent/CA2684172C/fr not_active Expired - Fee Related
- 2008-04-16 MX MX2009011285A patent/MX2009011285A/es active IP Right Grant
- 2008-04-16 JP JP2010503548A patent/JP5386477B2/ja not_active Expired - Fee Related
- 2008-04-16 SI SI200830270T patent/SI2150253T1/sl unknown
- 2008-04-16 PT PT08787962T patent/PT2150253E/pt unknown
- 2008-04-16 PL PL08787962T patent/PL2150253T3/pl unknown
- 2008-04-16 ME MEP-2009-298A patent/ME00934B/me unknown
- 2008-04-16 MY MYPI20094338A patent/MY146657A/en unknown
- 2008-04-16 WO PCT/FR2008/000533 patent/WO2008145840A2/fr not_active Ceased
- 2008-04-16 NZ NZ580483A patent/NZ580483A/en not_active IP Right Cessation
- 2008-04-16 DE DE602008005873T patent/DE602008005873D1/de active Active
- 2008-04-16 ES ES08787962T patent/ES2363056T3/es active Active
- 2008-04-16 HR HR20110459T patent/HRP20110459T1/hr unknown
- 2008-04-16 EA EA200970969A patent/EA015355B1/ru not_active IP Right Cessation
- 2008-04-16 EP EP08787962A patent/EP2150253B1/de active Active
- 2008-04-16 KR KR1020097021624A patent/KR101470043B1/ko not_active Expired - Fee Related
- 2008-04-16 CN CN2008800125419A patent/CN101674829B/zh not_active Expired - Fee Related
- 2008-04-17 JO JO2008185A patent/JO2662B1/en active
- 2008-04-17 TW TW097114000A patent/TWI411435B/zh not_active IP Right Cessation
- 2008-04-18 UY UY31033A patent/UY31033A1/es not_active Application Discontinuation
- 2008-04-18 CL CL2008001134A patent/CL2008001134A1/es unknown
- 2008-04-18 AR ARP080101600A patent/AR066106A1/es unknown
- 2008-04-18 PY PY200808013253A patent/PY08013253A/es unknown
2009
- 2009-10-05 US US12/573,316 patent/US8592443B2/en not_active Expired - Fee Related
- 2009-10-11 IL IL201451A patent/IL201451A/en not_active IP Right Cessation
- 2009-11-10 MA MA32335A patent/MA31369B1/fr unknown
2011
- 2011-06-28 CY CY20111100611T patent/CY1111779T1/el unknown

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Title
See references of WO2008145840A2 *

Also Published As

Publication number	Publication date
CN101674829B (zh)	2012-01-18
DK2150253T3 (da)	2011-07-25
ATE503481T1 (de)	2011-04-15
KR101470043B1 (ko)	2014-12-05
CY1111779T1 (el)	2015-10-07
US20100137370A1 (en)	2010-06-03
UY31033A1 (es)	2008-11-28
HK1142000A1 (en)	2010-11-26
ES2363056T3 (es)	2011-07-19
HRP20110459T1 (hr)	2011-07-31
WO2008145840A3 (fr)	2009-06-25
FR2915098A1 (fr)	2008-10-24
KR20090130063A (ko)	2009-12-17
WO2008145840A2 (fr)	2008-12-04
CN101674829A (zh)	2010-03-17
PA8776601A1 (es)	2008-11-19
PY08013253A (es)	2013-08-01
EA015355B1 (ru)	2011-06-30
JP5386477B2 (ja)	2014-01-15
DE602008005873D1 (de)	2011-05-12
BRPI0810446A2 (pt)	2014-10-14
ME00934B (me)	2012-06-20
TW200911248A (en)	2009-03-16
PT2150253E (pt)	2011-06-17
CL2008001134A1 (es)	2009-01-16
US8592443B2 (en)	2013-11-26
FR2915098B1 (fr)	2009-06-05
MA31369B1 (fr)	2010-05-03
CA2684172C (fr)	2015-10-27
EA200970969A1 (ru)	2010-02-26
JP2010524905A (ja)	2010-07-22
NZ580483A (en)	2011-06-30
CA2684172A1 (fr)	2008-12-04
EP2150253B1 (de)	2011-03-30
AR066106A1 (es)	2009-07-22
IL201451A (en)	2013-04-30
JO2662B1 (en)	2012-06-17
SI2150253T1 (sl)	2011-07-29
AU2008257321A1 (en)	2008-12-04
PL2150253T3 (pl)	2011-08-31
MY146657A (en)	2012-09-14
AU2008257321B2 (en)	2013-08-15
TWI411435B (zh)	2013-10-11
MX2009011285A (es)	2009-11-02
IL201451A0 (en)	2010-05-31

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